Antifungal Agents

Fen-Fei Gao
Overview

 Fungal infections classification:

 Superficial infections: Ringworm (tinea) → skin and mucous
membrane. Incidence rate is high.
 Systemic infections: Candida albicans → opportunist infections.
Fatality rate is high.
 Antifungal agents classification:
 Antibiotics: Amphotericin B;
 Azole: Ketoconazole;
 Allylamine: Terbinafine;
 Pyrimidine: Flucytosine.
Antibiotic Antifungal Drugs

 Polyenes: The polyene antibiotics bind with sterols in the fungal

cell membrane, principally ergosterol. This causes the cell's
contents to leak out and the cell dies. Animal cells contain
cholesterol instead of ergosterol and so they are much less
susceptible.
 Nystatin, Amphotericin B (may be administered liposomally),
Natamycin, Rimocidin, Filipin, Pimaricin

 Non-polyenes: Griseofulvin
Amphotericin B

 Produced by Streptomyces
nodosus. Amphoteric polyene
macrolide.
 Pharmacological Effect: broad-
spectrum
 Mechanism: binds to ergosterol in
fungi (cholesterol in humans and
bacteria) to form pores
Amphotericin B : Pharmacokinetics:

 Poorly absorbed from the gastrointestinal

tract.
 More than 90% bound by serum proteins.
 Metabolized in liver, excreted slowly in the
urine.
Amphotericin B Adverse Effects:
 Infusion-Related Toxicity: fever, chills, muscle
spasms, vomiting, headache, hypotension.
 Slower Toxicity:
 Renal toxicity
 K+↓, Mg2+↓
 Anemia: erythropoietin (促红细胞生成素)↓
 Abnormalities of liver function
 Neurologic sequela
 Announcements:
 Administrationin advance of NSAIDs and Antihistamine
drug, Glucocorticoid
 Periodic Monitoring
Liposomal Amphotericin B

 Lipid
preparations reduce toxicity
without sacrificing efficacy.

 Lipidformulations distributes mostly in

reticular endothelial tissue (liver,
spleen, lung), but less in kidney.
Nysfungin

 Like Amphotericin B and has same mechanism of

action.
 Too toxic for parenteral administration, and is only
used topically (局部).
 Not absorbed from skin, mucous membranes, or the
gastrointestinal tract, so little significant toxicity.
Griseofulvin

 Derived from a species of penicillium.

 Fungistatic drug (抑菌剂).
 Insoluble.
 Administered in a microcrystalline form only using in
the systemic treatment of dermatophytosis (脚癣).
 Deposited in newly forming skin where it binds to
keratin (角蛋白), protecting the skin from new
infection.
Azoles

 Synthetic compounds.
 Classification: according to the number of nitrogen
atoms in the five-membered azole ring
 Imidazoles: Ketoconazole, Miconazole, Econazole,
Clotrimazole, Bifonazole
 Triazoles: Itraconazole, Fluconazol, Vorionazole →
systemic treatment
Mechanism of Action

 Reduction of ergosterol synthesis by inhibition of

fungal cytochrome P450 enzymes.
 Greater affinity for funfal than for human cytochrome
P450 enzymes.
 Imidazoles exhibit a lesser degree of specificity than
the triazoles, accounting for their higher incidence of
drug interactions and side effects.
Ketoconazole

 The first oral azole introduced into clinical use.

 Less selective for fungal P450
 Inhibition of human P450 interferes with biosynthesis of
adrenal and gonadal steroid hormones;
 Alter the metabolism of other drugs.
 Best absorbed at a low gastric pH.
Miconazole, Econazole, Clotrimazole

 Bioavailability is low by taking orally.

 Used topically.
Bifonazole

 Double inhibition, antifungal action is more powerful.

Itraconazole

 Its absorption is increased by food and by low gastric

pH.
 Treatment of dermatophytoses (皮真菌病) and
onychomycosis (甲真菌病).
 The only agent with significant activity against
aspergillus (曲霉菌) species.
Fluconazol

 Water solubility and good cerebrospinal fluid

penetration.
 The widest therapeutic index (治疗指数) of the azoles.
 Treatment and secondary prophylaxis (预防) of
cryptococcal meningitis （隐球菌脑膜炎 ）.
Vorionazole

 Available in an intreavenous and an oral formulation.

 Metabolism is predominantly hepatic, but the
propensity for inhibition of mammalian P450 appears
to be low.
 Similar to itraconazole in tits spectrum of action,
having good activity against candida species.
 More effective than itraconazole.
Acrylamide

 Include Naftifine and Terbinafine.

 non-competitive and reversible inhibitor of Squalene
epoxidase.
 Terbinafine is synthetic, oral formulation.
 Fungicidal （杀菌剂）
 Treatment of dermatophytoses, especially
onychomycosis, more effective than griseofulvin or
itraconazole.
Pyramine

 Flucytosine （5-FC）is a water-soluble pyrimidine

analog.
 Its spectrum of action is much narrower than that of
amphotericin B.
 Poorly protein-bound and penetrates well into all
body fluid aompartments, including the cerebrospinal
fluid.
 Mechanism
 5-FC (taken up by fungal cells via the enzyme cytosine permease) → 5-FU
→ F-dUMP and FUTP → inhibit DNA and RNA synthesis, respectively.
 Synergy (协同) with amphotericin B.
 Spectrum of action: Cryptococcus neoformans, some candida species,
and the dematiaceous molds that cause chromoblastomycosis.
 Not used as a single agent because of
its demonstrated synergy with other
agents and to avoid the development
of secondary resistance.
 Adverseeffects: result from
metabolism to fluorouracil (5-FU)
 Bonemarrow toxicity with anemia,
leukopenia, and thrombocytopenia